Zebrafish as a Neuroblastoma Model: Progress Made, Promise for the Future

Abstract

For nearly a decade, researchers in the field of pediatric oncology have been using zebrafish as a model for understanding the contributions of genetic alternations to the pathogenesis of neuroblastoma (NB), and exploring the molecular and cellular mechanisms that underlie neuroblastoma initiation and metastasis. In this review, we will enumerate and illustrate the key advantages of using the zebrafish model in NB research, which allows researchers to: monitor tumor development in real-time; robustly manipulate gene expression (either transiently or stably); rapidly evaluate the cooperative interactions of multiple genetic alterations to disease pathogenesis; and provide a highly efficient and low-cost methodology to screen for effective pharmaceutical interventions (both alone and in combination with one another). This review will then list some of the common challenges of using the zebrafish model and provide strategies for overcoming these difficulties. We have also included visual diagram and figures to illustrate the workflow of cancer model development in zebrafish and provide a summary comparison of commonly used animal models in cancer research, as well as key findings of cooperative contributions between MYCN and diverse singling pathways in NB pathogenesis.

Keywords: animal model; neuroblastoma; zebrafish.

Figure 1

An overview of the workflow using zebrafish model for NB study. Offspring from mating of wild-type (WT) or genetically engineered fish lines (A) can be subjected for (i) genome editing or transgene overexpression at one-cell stage (B), or (ii) transplantation of tumor cells at 2 days post fertilization for subsequent drug screening or functional analyses (C). The genetically modified embryos (B) can also be raised up for monitoring tumor development (D). Examples of crucial studies that can be performed using the zebrafish model are listed in the middle of the circle. This figure was created with BioRender.com.

Figure 2

Cooperative contributions of diverse signaling pathways to the pathogenesis of NB—findings from zebrafish models. Blue lines connect cooperative genes in NB pathogenesis; Blue arrows indicate positive impact; Bar-headed lines indicate inhibitory effect; and Black lines indicate synergy between drugs. ALK, anaplastic lymphoma kinase; arid1a, AT-rich interacting domain–containing protein 1A; c-MYC, V-Myc avian myelocytomatosis viral oncogene homolog; DEF, digestive organ expansion factor; EGFR, epidermal growth factor receptor; Gab2, GRB2-associated-binding protein 2; LIN28B, lin-28 homolog B; LMO1, LIM domain only 1; MYCN, V-Myc avian myelocytomatosis viral oncogene neuroblastoma; nf1, neurofibromatosis type 1; PAG2G4, proliferation-associated protein 2G4; and PTPN11, protein tyrosine phosphatase non-receptor type 11. This figure was created with BioRender.com.